https://doi.org/10.1177/2042018819875408 https://doi.org/10.1177/2042018819875408 Ther Adv Endocrinol Metab
2019, Vol. 10: 1–9 DOI: 10.1177/ 2042018819875408 © The Author(s), 2019. Article reuse guidelines: sagepub.com/journals-permissions
Therapeutic Advances in Endocrinology and Metabolism
journals.sagepub.com/home/tae 1
Introduction
Type 2 diabetes is one of the most prevalent chronic diseases in the Netherlands and exposes patients to a high risk of developing macrovascu-lar and microvascumacrovascu-lar complications.1,2 Guidelines
have been developed and repeatedly updated to implement evidence-based care to prevent vascu-lar complications.3–6 Unfortunately, to the best of
the authors’ knowledge no trials have been per-formed on the efficacy of the guideline nor the revised versions. In the DiaGene study, long-term follow up was available covering a period from no guideline up until to multiple revised
versions. Therefore, the authors had the unique opportunity to determine the real-time efficacy of the evolving diabetes guideline, with the expecta-tion that promoting structured diabetes care reduced the risk of vascular complications of type 2 diabetes.
Risk factors of macrovascular and microvascular complications in type 2 diabetes include hyper-glycemia,1 hypertension,7 lifestyle,8 smoking,
and hypercholesterolemia.9 In addition to
pre-venting acute complications of type 2 diabetes, the objective of treatment is to reduce morbidity
The effect of guideline revisions on vascular
complications of type 2 diabetes
Ralph Heijmans, Sunny S. Singh, Aloysius G. Lieverse, Eric J.G. Sijbrands and Mandy van Hoek
Abstract
Background: The aim of this study was to investigate the impact of implementation and revision
of the ‘Diabetes Mellitus type II’ guideline by the Dutch College of General Practitioners (DCGP) on the prevalence and incidence of macrovascular and microvascular complications.
Methods: The DiaGene study is a case-control study (n = 1886 patients of type 2 diabetes)
with extensive, retrospectively collected complication data, as well as prospective follow up of complications. The study incorporates all lines of diabetes care. Cases were divided into categories according to the date of onset of diabetes and publication dates of the DCGP. Logistic regression models were used to investigate the associations between guideline version and complications. To investigate a possible trend between guideline version and complications, the ‘guideline category’ was also used as a continuous variable. All models were adjusted for clinical covariables.
Results: The 1999 and 2006 guidelines versions were associated with significantly lower risk
of retinopathy than the group that started without a guideline [OR 0.32 (95% CI 0.14–0.72, p = 0.006) and 0.31 (95% CI 0.11–0.91, p = 0.034), respectively]. A significant trend in reduction of peripheral artery disease (PAD) over the guideline versions was found, adjusted for age, sex and diabetes duration (odds ratio (OR) 0.70, 95% CI 0.51-0.97, p trend = 0.029) and for retinopathy in all models (OR = 0.52, 95% CI 0.37-0.73, p trend < 0.001).
Conclusions: The introduction of the first diabetes guideline and subsequent revisions have
reduced the risk of macrovascular and microvascular complications of type 2 diabetes, most strongly in diabetic retinopathy. This indicates that real-time diabetes care has improved over time.
Keywords: diabetes care, diabetic retinopathy, guideline, macrovascular complications,
microvascular complications, type 2 diabetes
Received: 3 June 2019; revised manuscript accepted: 8 August 2019.
Correspondence to:
Mandy van Hoek
Department of Internal Medicine, Erasmus Medical Center, PO-box 2040, 3000 CA Rotterdam, The Netherlands m.vanhoek@erasmusmc.nl Ralph Heijmans Sunny S. Singh Eric J.G. Sijbrands Department of Internal Medicine, Erasmus MC - University Medical Center, Rotterdam, The Netherlands
Aloysius G. Lieverse
Department of Internal Medicine, Maxima Medical Center, Eindhoven, The Netherlands
and mortality by preventing or delaying vascular complications.10 Therefore, diabetes guidelines
aim at regulating blood glucose levels and influ-encing the cardiovascular risk factors by control-ling blood pressure, blood lipid levels, and improving lifestyle behavior.6
The Dutch College of General Practitioners (DCGP)3 published their first guideline ‘Diabetes
Mellitus type II’ in 1989. This guideline con-tained evidence-based recommendations for pri-mary care concerning diagnosis, treatment, and support of patients with type 2 diabetes aimed at a uniform approach to diabetes care.5 In order to
meet new standards and to integrate new scien-tific evidence, the diabetes guideline has been updated three times, in 1999, 2006, and 2013.4–6
Guidelines on treatment of type 2 diabetes in sec-ondary healthcare were not available in the Netherlands until 2013.11 Therefore, the
guide-lines of the DCGP were also used in hospitals. In a small number of studies, the effect of up to date worldwide and local diabetes guidelines on medical diabetes therapy has been determined.12–14
The guideline revisions were associated with a sig-nificantly increased use of antidiabetic medica-tion. Apparently, the treatment recommendations were quickly put into clinical practice.12–14
However, the effect of diabetes guidelines on patient’s clinical outcomes has not been investi-gated directly.
In the DiaGene study, the authors investigated the efficacy of the implementation and revision of the guideline ‘Diabetes Mellitus type II’ of the DCGP on macrovascular and microvascular complications. Materials and methods
Study design
The design of the DiaGene study has been described previously.15 The DiaGene study is an
all lines of healthcare case-control study with pro-spective follow up, designed to investigate the eti-ology of type 2 diabetes and its vascular complications. Data was collected in the cities of Eindhoven and Veldhoven, the Netherlands. The majority of patients with type 2 diabetes in the area of Eindhoven, both primary care and outpa-tient clinic, were approached for inclusion. Type 2 diabetes was diagnosed according to the guidelines of the WHO and the American
Diabetes Association.16,17 In total, 1886 patients
with type 2 diabetes were included in the study. Written informed consent was obtained from all participants. This study was approved by the Medical Ethics Committee of the Erasmus MC and the local Ethics Committees of the hospitals in Eindhoven.
Definitions of macrovascular and microvascular complications
The definitions of macrovascular and microvas-cular complications have previously been described in more detail.15 Ischemic heart disease
(IHD) was defined as myocardial infarction or percutaneous coronary intervention/coronary artery bypass graft (PCI/CABG). Ischemic cere-bral disease (ICD) included cerebrovascular acci-dent or transient ischemic attack. Peripheral arterial disease (PAD) was defined as an ankle-brachial index below 0.80 or below 0.90 with typi-cal complaints, any intervention to treat PAD or the self-reported presence of intermittent claudi-cation. IHD, ICD, and PAD were all derived from medical records and questionnaires. Diabetic retinopathy was scored and graded according to the report of an ophthalmologist and fundus pho-tography. Diabetic nephropathy was defined as microalbuminuria [albumin/creatinine ratio (ACR) ⩾2.5 for men or ⩾3.5 for women] present at two of three consecutive measurements, or when high micro-albuminuria or macro-albumi-nuria was present at one measurement (ACR ⩾ 12.5 for men or ⩾17.5 for women). Diabetic neuropathy was defined by a podiatrist, neurolo-gist or the patient’s treating physician. Prospective follow up for macrovascular and microvascular endpoints, according to the definitions above, was performed through the medical charts of all hospi-tals in the region of Eindhoven. Questionnaires were sent to the primary care patients, who were not under treatment in the local hospitals, to reduce the chance of missing a vascular event. In the authors’ analyses, data on complications during baseline and follow up were merged, and classified as follows: patients with complications at baseline and/or during follow up were qualified as having complications, patients without compli-cations at baseline and during follow up were qualified as having no complications, patients with missing data at baseline or during follow up but with known complications on either two moments were qualified as having complications,
and patients with missing data at baseline and no complications during follow up were qualified as missing. Finally, patients with no complications at baseline and missing data during follow up were qualified as having no complications. The latter mainly belonged to primary care and failed to respond to the prospective questionnaire. For all of these patients, a screening of hospital records inside the region was performed. However, as this system may not be foolproof, the authors additionally randomly contacted 40 of these patients and found complications at follow up in 5% indicating an overall acceptable error in the study of <2.1% misclassification.
Exposure to guideline groups
The date of birth and age of onset of type 2 diabe-tes were used to determine the year of onset of type 2 diabetes. Subsequently, as a measure for treatment according to versions of the guideline, all cases were divided into categories in alignment with the publications of the DCGP guideline ‘Diabetes Mellitus type II’ as follows: patients with onset diabetes before 1989 in category 1, patients with onset diabetes during or after 1989 and before 1999 in category 2, patients with onset diabetes during or after 1999 and before 2006 in category 3, and patients with onset diabetes dur-ing or after 2006 and before 2013 in category 4. There were no patients in the DiaGene study with the onset of type 2 diabetes after 2012. These categories reflect groups of people that have pro-gressed through and have been treated accord-ing to the subsequent guidelines for a certain period in each category. As explained in the fol-lowing, to reduce confounding by the age and duration of diabetes, the authors adjusted the logistic models accordingly.
Statistical methods
To compare baseline variables between the four guideline categories, the one-way analysis of vari-ance (ANOVA) test was applied for continuous variables with a normal distribution and the chi-squared test for categorical variables.
Logistic regression models were used to investi-gate the associations between the macrovascular and microvascular complications as outcome var-iables and the guideline categories as the expo-sure variable. To investigate a possible trend between guideline version and complications, the
‘ guideline category’ was also used as a continuous variable in the regression models.
Two models were conducted. The basic model 1, was adjusted for sex, age, and duration of type 2 diabetes and an extended model 2 was addition-ally adjusted for body mass index (BMI) and smoking. Statistical analyses were performed using IBM SPSS Statistics, version 25.
Results
Baseline characteristics
Baseline characteristics of cases, which were divided among the four categories according to guideline version, are listed in Table 1. A total of 120 cases were excluded because the date of onset diabetes could not be determined, leaving a total of 1766 patients for analyses. There was a significant difference in age, HbA1c, HDL-cholesterol, non-HDL-cholesterol, smoking, and the prevalence of all macrovascular and microvascular complications between guideline versions. The distribution of sex was not different over the guideline categories.
Association between guideline version and vascular complications
The results of the logistic regression analyses for the basic and extensive models are listed in Table 2. Compared with the reference category ‘no guide-line’, the odds ratio (OR) of having IHD, ICD, or PAD did not differ significantly in all guideline cat-egories in the basic and extensive models.
With regard to the microvascular complications diabetic nephropathy and neuropathy, the OR in both models did not differ significantly in the guideline categories compared with the ‘no guideline’ category. For diabetic retinopathy, in the most extensive model, the 1999 and 2006 guideline categories were associated with a lower significant ORs of 0.32 (95% CI 0.14– 0.72, p = 0.006) and 0.31 (95% CI 0.11–0.91, p = 0.034), respectively.
Effect of guideline updates on vascular complications
In Table 3 trend associations between guideline versions and vascular complications are sted. PAD was significantly reduced overall guideline versions in model 1 (OR 0.70, 95% CI 0.51–0.97,
p trend = 0.029). No other significant trends were found for macrovascular complications.
With regard to microvascular complications, a significant trend in reduction of diabetic retin-opathy was found overall guideline categories in model 1 (OR 0.56, 95% CI 0.41–0.77, p trend < 0.001) and model 2 (OR 0.52, 95% CI 0.37–0.73, p trend < 0.001). No significant trends were found for other microvascular complications.
Discussion
In this study, the authors found a significant risk reduction of 69% of diabetic retinopathy when
patients started their treatment in a more recent DCGP type 2 diabetes guideline. In addition, the authors detected a significant overall trend in lower odds for PAD and diabetic retinopathy when starting treatment in a more recent DCGP guideline.
The authors’ results demonstrate that diabetes care has improved over time. The authors pre-sume these effects can be explained by two fac-tors. First, guideline implementation eliminates the uncertainty of clinicians with regards to treat-ment method, avert outdated practices and improve the consistency of care.18 Second,
guide-line revisions reflect the scientific development of type 2 diabetes care over the years, which is
Table 1. Baseline characteristics.
Variable No guideline Guideline 1989 Guideline 1999 Guideline 2006 p value
n = 242 n = 579 n = 757 n = 188
Age (years) 70.4 ± 9.1 66.1 ± 9.6 63.4 ± 10.7 61.1 ± 11.6 <0.001 Sex (male count (%)) 129 (53.3) 300 (51.8) 411 (54.3) 111 (59.0) 0.377 Duration of type 2 diabetes (years) 26.2 ± 6.8 13.1 ± 3.2 4.9 ± 2.4 1.0 ± 1.0 <0.001 BMI (kg/m2) 30.3 ± 5.4 30.9 ± 5.9 30.4 ± 5.2 29.9 ± 5.0 0.123 HbA1c (mmol/mol) 57.49 ± 10.89 56.98 ± 12.31 50.90 ± 10.62 50.10 ± 11.95 <0.001 HbA1c (%) 7.41 ± 1.00 7.36 ± 1.13 6.81 ± 0.97 6.73 ± 1.09 <0.001 HDL-cholesterol (mmol/l) 1.25 ± 0.39 1.17 ± 0.32 1.16 ± 0.31 1.11 ± 0.29 <0.001 Non-HDL-cholesterol (mmol/l) 2.84 ± 0.75 3.06 ± 0.89 3.17 ± 0.89 3.40 ± 1.01 <0.001 Current smoker (%) 28 (13.1) 100 (18.9) 125 (18.1) 31 (18.3) 0.045 Former smoker (%) 120 (56.3) 285 (53.9) 392 (56.8) 109 (64.5) Never smoked (%) 65 (30.5) 144 (27.2) 173 (25.1) 29 (17.2)
Ischemic heart disease (%) 37.9 36.1 25.3 30.3 <0.001 Ischemic cerebral disease (%) 24.2 15.1 14.4 13.1 0.003 Peripheral artery disease (%) 22.9 20.7 13.4 10.3 <0.001 Nephropathy (%) 51.9 43.5 37.7 30.1 <0.001 Retinopathy (%) 69.0 44.5 13.7 12.0 <0.001 Neuropathy (%) 76.5 59.7 63.3 48.7 <0.001
Unless stated otherwise, mean (±SD) are given.
Tabl
e 2.
Guideline c
at
egories and the as
sociation with v ascular c omplic ation risk. Guideline 1989 Guideline 1999 Guideline 2006 Model 1 Model 2 Model 1 Model 2 Model 1 Model 2 OR (95% CI) p v alue OR (95% CI) p v alue OR (95% CI) p v alue OR (95% CI) p v alue OR (95% CI) p v alue OR (95% CI) p v alue IHD 1.19 (0.71–1.98) 0.509 0.94 (0.53–1.65) 0.824 0.77 (0.38–1.58) 0.480 0.54 (0.25–1.17) 0.116 1.09 (0.46–2.59) 0.846 0.74 (0.29–1.90) 0.528 ICD 0.56 (0.31–1.02) 0.060 0.61 (0.32–1.17) 0.137 0.53 (0.23–1.22) 0.136 0.58 (0.24–1.43) 0.238 0.48 (0.17–1.35) 0.164 0.55 (0.18–1.69) 0.296 PAD 1.00 (0.56–1.80) 0.993 0.94 (0.49–1.78) 0.848 0.63 (0.28–1.42) 0.264 0.59 (0.24–1.43) 0.242 0.48 (0.17–1.36) 0.167 0.48 (0.16–1.50) 0.208 Nephropathy 0.92 (0.56–1.50) 0.726 0.78 (0.46–1.34) 0.373 0.79 (0.40–1.57) 0.503 0.75 (0.36–1.58) 0.451 0.60 (0.26–1.38) 0.227 0.50 (0.20–1.27) 0.146 Retinopathy 0.93 (0.55–1.58) 0.800 0.89 (0.50–1.57) 0.683 0.33 (0.16–0.72) 0.005* 0.32 (0.14–0.72) 0.006* 0.39 (0.14–1.03) 0.057 0.31 (0.11–0.91) 0.034* Neuropathy 0.71 (0.37–1.37) 0.308 0.75 (0.37–1.53) 0.434 1.14 (0.45–2.90) 0.776 1.27 (0.48–3.39) 0.632 0.75 (0.21–2.66) 0.660 0.71 (0.19–2.71) 0.618 Model 1 adjus ted f or se
x, age, and dur
ation of type 2 diabet
es. Model 2 additionall y adjus ted f or body mas s inde x, and smoking. ICD, ischemic c er ebr
al disease; IHD, ischemic heart disease; P
AD, peripher al art erial disease. *p v alue < 0.05
expected to improve clinical outcomes, although the findings were not entirely consistent with the observations, upon which these revisions are based. The DCGP published the first type 2 diabetes guideline in 1989.3 This guideline contained
recommendations for the diagnosis and treat-ment of type 2 diabetes in primary care. The main goals of treatment in this guideline were the regulation of blood glucose levels and the reduction of body weight. Of note, the precise treatment targets of blood sugar and body weight remained unclear. In 1999, the first revision was published.4 An important change was the advice
to regulate glucose levels more intensively based on the UKPDS 33 study,19 in which intensive
blood glucose control substantially decreased the risk of the microvascular but not of the mac-rovascular complications. Therefore, the authors expected a decrease of microvascular complica-tion risk following the introduccomplica-tion of the 1999 guideline. This was only partly the case. For dia-betic retinopathy, the authors found a significant risk reduction in the 1999 guideline category, but no significant risk reduction for nephropathy and neuropathy. Another important change in this 1999 revision was the treatment advice for hyper-tension and lipid metabolism disorders. Thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and cholesterol synthe-sis inhibitors (statins) were prescribed according to risk scores based on the UKPDS 387 and the
4S study.20 The UKPDS 38 study demonstrated
that tight blood pressure control decreased the risk of ICD. Our results, however, did not show a significant change in ICD after implementation
of the 1999 guideline. Tight blood pressure con-trol was also associated with a reduced risk of dia-betic retinopathy, but not of diadia-betic nephropathy and neuropathy, which corresponds to the authors’ results. The 4S study revealed that cho-lesterol-lowering simvastatin decreased the risk of IHD events in high-risk patients and type 2 diabe-tes was considered as cardiovascular risk equiva-lent.21,22 However, IHD risk did not improve in the
authors’ analysis, but a significant trend for better prevention of PAD over the guideline versions was found. Finally, in the 1999 guideline, recommen-dations were formulated for the detection of patients with diabetes in high-risk populations. This may have decreased the delay between the onset and the diagnosis of diabetes, leading to an early start of treatment and, as a consequence, improved the prevention of vascular complications, as found for PAD and retinopathy in our study. In 2006, the second revision was published.5
Based on the Heart Protection Study,23
prescrip-tions of statins to all patients with type 2 diabetes was recommended. In this study, however, no significant further risk reduction in IHD and ICD risk was found when treatment was started according to the 2006 guideline. This guideline version also emphasized the importance of pro-tecting renal function and diagnosing diabetic neuropathy. In this study, no changes in nephrop-athy and neuropnephrop-athy risk were observed.
According to the authors’ findings, it can be concluded that guideline implementation and revisions have prevented PAD and diabetic retin-opathy in the study patients with type 2 diabetes.
Table 3. Odds ratios (ORs) and associated p values after trend logistic regression analyses.
Guideline category (model 1) Guideline category (model 2)
OR (95% CI) p trend OR (95% CI) p trend
Ischemic heart disease 0.93 (0.71–1.20) 0.567 0.84 (0.63–1.11) 0.218 Ischemic cerebral disease 0.88 (0.64–1.22) 0.448 0.91 (0.65–1.29) 0.599 Peripheral arterial disease 0.70 (0.51–0.97) 0.029 0.71 (0.50–1.00) 0.053 Nephropathy 0.82 (0.64–1.06) 0.126 0.83 (0.63–1.09) 0.173 Retinopathy 0.56 (0.41–0.77) <0.001 0.52 (0.37–0.73) <0.001 Neuropathy 1.16 (0.80–1.69) 0.441 1.17 (0.79–1.73) 0.446
Model 1 adjusted for sex, age, and duration of type 2 diabetes. Model 2 additionally adjusted for BMI and smoking.
There are advantages and disadvantages of this study to consider to aid in the interpretation of the findings. An advantage of this study is the meticulous collection of phenotypic, medications, and risk factor data. In addition, to the best of the authors’ knowledge, this is the first time the effects of diabetes guidelines on patient’s clinical outcomes have been investigated in a real-world clinical setting. Although guidelines are based on scientific insights obtained by epidemiologic reports and large controlled trials and changes in prescription of anti-hyperglycemic drugs after revision of guidelines have been examined,12–14 to
the best of the authors’ knowledge, no study has been carried out that directly investigates the effect of guideline implementation and revision on type 2 diabetes complications. Although this study was performed with great care, some limita-tions need to be considered. First, diabetic neu-ropathy data was only available for patients that were under surveillance in the hospitals. This reduced the power for the analyses as well as gen-eralizability to nonhospital patients. Second, owing to the characteristic features of a cohort study, patients of the ‘no guideline’ category were also exposed to the first, second, and third guide-line. The authors’ main analyses, therefore, com-pared patients treated without a guideline which followed treatment according to 1989, 1999, and 2006 guidelines with patients treated according to 1989, 1999, and 2006 guidelines. It is possible that the effect of treatment without guideline or treatment according to an earlier guideline is compensated by exposure to later guidelines. This may have reduced the estimates of the effi-cacy of the guidelines in these analyses. In addi-tion, the characteristics of a cohort study also entail a possible selection bias: one could argue that the sickest individuals from the oldest guide-line categories have not been included in our study. As a consequence, the number of events in the older guideline groups may have been under-estimated. Despite this, the authors still found significant improvement in PAD and retinopathy after implementing and updating the guideline. Third, the duration of diabetes and age are impor-tant risk factors for developing complications. It is therefore essential to adjust the models accord-ingly. However, diabetes duration and age are also directly associated with guideline category. Adjustment for diabetes duration and age could, therefore, lead to an underestimation of the effect of guideline implementation. Despite these
adjustments, the authors were still able to show the effects of PAD and diabetic retinopathy in the main analysis. Fourth, a proportion of the DiaGene study consists of secondary care patients. The original type 2 diabetes guideline and further revisions published by the DCGP were aimed at primary care. Guidelines regarding secondary care treatment were not available until 2013.11 The majority of the patients in this study
initially started their treatment in primary care and the DCGP guidelines have also been used for treatment in secondary care. Finally, the authors cannot exclude the fact that the socio-economic developments since 1989 also played a role. Model 2 was additionally adjusted for smoking and BMI at inclusion, to adjust for lifestyle fac-tors. However, residual lifestyle effects cannot be excluded. Furthermore, the fact that the BMI of some participants changes significantly over time cannot be excluded. Although BMI was highly stable in the vast majority of participants of a number of long-term follow-up studies.24,25
To conclude, this study shows that for patients with type 2 diabetes, guideline adjustments through the years have significantly reduced PAD and retinopathy. This indicates that real-time dia-betes care has improved over time. Future studies should be directed at investigating the effect of guideline implementation in other diseases. In addition, in future diabetes guideline studies, when exact dates of complications are available, associa-tions between complication incidence rate among different guideline categories can give an even more accurate estimate of guideline update effects. Author note
RH analyzed and completed the database, wrote and reviewed/edited manuscript.
SS maintained the DiaGene study database, ana-lyzed the data, wrote and reviewed/edited the manuscript.
AL collected and designed the DiaGene study and reviewed and edited the manuscript.
ES collected and designed the DiaGene study, initiated the research question, and reviewed and edited the manuscript.
MH coordinated the analyses, initiated the research question, collected data, designed the DiaGene study, and wrote, reviewed, and edited the manuscript.
All authors have read and approved the final manuscript
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors declare no conflicts of interest in preparing this article.
ORCID iD
Mandy van Hoek https://orcid.org/0000 -0002-2957-5436
References
1. Stratton IM, Adler AI, Neil HA, et al.
Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.
BMJ 2000; 321: 405–412.
2. Kennel WB and McGee DL. Diabetes and cardiovascular disease. The Framingham study.
JAMA 1979; 241: 2035–2038.
3. Cromme PMJ, Rutten G, Zuidweg J, et al. NHG Standaard Diabetes mellitus type II. Huisarts Wet 1989: 509–512.
4. Rutten GVS, Heine R, Grauw WJ, et al. NHG-Standaard Diabetes mellitus type 2 (eerste herziening). Huisarts Wet 1999; 42: 67–84. 5. Rutten GGW, Nijpels G, Goudswaard A,
et al. NHG-Standaard Diabetes mellitus type
2 (tweede herziening). Huisarts Wet 2006; 49: 137–152.
6. Rutten GE, De Grauw WJ, Nijpels G, et al. NHG-Standaard Diabetes mellitus type 2 (derde herziening). Huisarts Wet 2013; 56: 512–525. 7. Tight blood pressure control and risk of
macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998; 317: 703–713.
8. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343–1350. 9. Stamler J, Vaccaro O, Neaton JD, et al. Diabetes,
other risk factors, and 12-yr cardiovascular mortality for men screened in the multiple risk
factor intervention trial. Diabetes Care 1993; 16: 434–444.
10. Marathe PH, Gao HX and Close KL. American diabetes association standards of medical care in diabetes 2017. J Diabetes 2017; 9: 320–324. 11. Vereniging NI. Richtlijn Diabetes Mellitus. 2013;
1–13. Retrieved from https://www.internisten. nl/sites/internisten.nl/files/uploads/A_/zK/A_ zKUbVPPyd3CmH-mbz4PA/richtlijn_2013_-Diabetes-Mellitus-Inleiding-en-methodiek.pdf 12. Lub R, Denig P, van den Berg PB, et al. The
impact of new insights and revised practice guidelines on prescribing drugs in the treatment of Type 2 diabetes mellitus. Br J Clin Pharmacol 2006; 62: 660–665.
13. Stalhammar J, Berne C and Svardsudd K. Do guidelines matter? A population-based study of diabetes drug use during 20 years. Scand J Prim
Health Care 2001; 19: 163–169.
14. Langendam MW, Hooijkaas C and Piepenbrink JF. The increase in the use of drug treatment for diabetes mellitus in the Netherlands, 1998-2003.
Ned Tijdschr Geneeskd 2006; 150: 1396–1401.
15. van Herpt TTW, Lemmers RFH, van Hoek M,
et al. Introduction of the DiaGene study: clinical
characteristics, pathophysiology and determinants of vascular complications of type 2 diabetes.
Diabetol Metab Syndr 2017; 9: 47.
16. Alberti KG and Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998; 15: 539–553. 17. Report of the expert committee on the diagnosis
and classification of diabetes mellitus. Diabetes
Care 1997; 20: 1183–1197.
18. Woolf SH, Grol R, Hutchinson A, et al. Clinical guidelines: potential benefits, limitations, and harms of clinical guidelines. BMJ 1999; 318: 527–530.
19. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 837–853. 20. Pyorala K, Pedersen TR, Kjekshus J, et al.
Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian simvastatin survival study (4S). Diabetes Care 1997; 20: 614–620.
21. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian simvastatin survival study (4S).
Lancet 1994; 344: 1383–1389.
22. Khaw KT, Wareham N, Luben R, et al. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European prospective investigation of cancer and nutrition (EPIC-Norfolk). BMJ 2001; 322: 15–18.
23. Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol
lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 360: 7–22.
24. Vistisen D, Witte DR, Tabak AG, et al. Patterns of obesity development before the diagnosis of type 2 diabetes: the Whitehall II cohort study.
PLoS Med 2014; 11: e1001602.
25. Dhana K, van Rosmalen J, Vistisen D, et al. Trajectories of body mass index before the diagnosis of cardiovascular disease: a latent class trajectory analysis. Eur J Epidemiol 2016; 31: 583–592.
Visit SAGE journals online journals.sagepub.com/ home/tae
